The present invention relates to a method and apparatus for uniformly mixing liquid samples, reagents, or other solutions in a container. In particular, the present invention provides a method for rapidly and uniformly mixing a liquid by using a pair of magnetic field sources rotating near the sides of the container to generate a vortex mixing action within the liquid.
Automated microbiology and clinical chemistry analyzers identify the presence of microorganisms and analytes in body fluids such as urine, blood serum, plasma, cerebrospinal fluid, sputum and the like. Automated microbiology and clinical chemistry analyzers improve productivity and enable the clinical laboratory to meet the workload resulting from high-test volume. Automated systems provide faster and more accurate results as well as valuable information to clinicians with regard to the types of antibiotics or medicines that can effectively treat patients diagnosed with infections or diseases. In a fully automated analyzer, many different processes are required to identify microorganisms or analytes and an effective type of antibiotic or medicine. Throughout these processes, patient liquid samples and samples in combination with various liquid reagents and antibiotics, are frequently required to be mixed to a high degree of uniformity producing a demand for high speed, low cost mixers that occupy a minimal amount of space.
Analyzers like those described above perform a variety of analytical processes upon microbiological liquid samples and in most of these, it is critical that a patient""s biological sample, particularly when in a liquid state, be uniformly mixed with analytical reagents or diluent or other liquids or even re-hydrated compositions and presented to an analytical module in a uniformly mixed state. In a biochemical analyzer, other liquids like broth may need to be uniformly stirred before being used. Various methods have been implemented to provide a uniform sample solution mixture, including agitation, mixing, ball milling, etc.
One popular approach involves using a pipette to alternately aspirate and release a portion of liquid solution within a liquid container. Magnetic mixing, in which a vortex mixing action is introduced into a solution of liquid sample and liquid or non-dissolving reagents, herein called a sample liquid solution, has also been particularly useful in clinical and laboratory devices. Typically, such magnetic mixing involves rotating or revolving a magnetic field beneath the bottom of a container so as to cause a magnetically susceptible mixing member to rotate in a generally circular path in a plane inside the container at the bottom of the container. Thus, such magnetic mixers require that a magnetically susceptible mixing member be placed in close proximity, essentially in physical contact, with the bottom of the container.
Magnetic mixers that cause a magnetically susceptible mixing member to rotate or revolve at the bottom level or top level of liquid in a container are not useable in the instance of so-called xe2x80x9cfalse-bottomxe2x80x9d sample containers. False-bottom containers have the same general size as standard containers, but have an additional false bottom located at a predetermined distance above the physical bottom of the container. False-bottom containers are advantageously employed in several instances, for instance when it is desired to decrease the physical size of aspiration means which extract patient sample from a container. In such cases, the vertical travel required by the aspirator is decreased as the liquid sample level is found nearer the top of its container. Using false-bottom containers also makes it possible to handle smaller-than-normal liquid samples in containers that also have an extended surface for carrying bar-code indicia. In other instances and for various reasons, only a small volume of a patient""s sample may be available and false-bottom containers makes it possible to transport a smaller-than-normal sample volume within an automated analyzer without having special handling devices adapted to operate on smaller-than-normal sample containers. Alternately, in the instance of magnetic vortex mixing, it may be desirable for reasons of mixing efficiency to have the source of mixing energy, the mixing member, located anywhere within the volume of a sample to be mixed as opposed to having the mixing member located at either the top or bottom of the sample container. Even further, it may be desirable for reasons of mixing efficiency for the source of rotational energy to be vertically moveable relative to the sample liquid during the mixing process as opposed to having the mixing member located in a stationary plane within the sample container.
U.S. Pat. No. 5,586,823 describes a magnetic stirrer comprising a bottle having a base and a stirrer bar of relatively low power magnetization lying on the bottle base. A permanent magnet of relatively high power is located beneath and close to the bottle base, and means for continuously rotating the external permanent magnet about an axis substantially normal to the bottle base. The rotating magnetic field causes the stirrer bar to continuously rotate within the liquid in a plane parallel to and above the bottle base.
U.S. Pat. No. 5,547,280 discloses a two-part housing magnetic stirrer having a lower drive and an upper part that forms a mounting surface for a sample container having a mixing magnet. The separating surface of the upper and lower parts are approximately horizontal in the working position. The upper part is made of glass and, when in its working position, is tightly pressed against an opposing surface of the lower part to provide a magnetic stirrer that is sealed against aggressive vapors.
U.S. Pat. No. 5,078,969 discloses a stirrer which is placed on a reaction vessel and used for staining biological specimens on microscope slides in a jar. The bottom wall of the jar is perforated and made of glass so that the magnetic flux passes through to couple a stirrer rod to a magnetic drive arm. The jar is seated on a platform with the magnetic-stirrer drive mounted and operable below the platform. The magnetic drive has a motor with magnetic drive arm like a permanent magnetic and a variable speed control device to control the angular velocity of the magnetic arm.
U.S. Pat. No. 4,728,500 discloses a stirrer comprising a magnetically permeable vessel containing at least one magnetic bead and a magnetic device having a spacer with a number of longitudinally positioned magnetic bars parallel to one another disposed thereon. The bars may be moved in a longitudinal direction beneath the vessel so as to produce an oscillating magnetic field causing the beads to undergo an elliptic motion.
U.S. Pat. No. 4,534,656 discloses a magnetic stirrer apparatus in which the stirrer is buoyant, and thereby floats on the surface of a liquid which is to be stirred. The stirrer is caused to be rotated, generally about the vertical axis of the flask, and is enabled to change its elevation, relative to the bottom of the flask, as the level of liquid in the flask is changed. The floating stirrer is restricted by a guide rod to rotational movement, and to vertical movement as the liquid level changes; a magnetic drive is provided to cause rotational movement of the stirrer, thereby to mix the liquid in the flask.
U.S. Pat. No. 4,162,855 discloses a magnetic rotor having a central hub which has a surface covered with an inherently high lubricity material and on which is mounted a radially extending magnetic impeller. The magnetic rotor is mounted in a central collar portion of a cage which has a number of frame members extending from the collar to prevent the rotating impeller from engaging the walls of the vessel. As the outward members maintain the cage in position within the vessel, the magnetic rotor is allowed to xe2x80x9cfloatxe2x80x9d relative to the cage and rotate freely, with extremely low frictional forces, relative to the vessel to agitate the substance therein.
Accordingly, from a study of the different magnetic mixers available in the prior art, there is an unmet need for an improved magnetic vortex mixer capable of magnetically mixing small volume liquid samples held within false-bottom containers. In addition, there is a need for a magnetic mixer which provides a uniform mixing action within liquid samples contained in false-bottom tubes held in a sample tube rack without removing the sample tubes from the rack so as to eliminate the need for time-consuming and spacious mechanisms to move the tube to a separate location for mixing. There is a further need for magnetic mixing method having increased efficiency by moving the mixing member along an axis of the sample container during the mixing process, as may be required for low viscosity liquid samples.
Many of these disadvantages to the prior art are overcome by using the apparatus and/or methods of this invention. This invention provides a method for mixing a liquid solution contained in a container by causing a freely disposed, magnetically susceptible mixing member to rotate or revolve in a generally circular pattern in a plane above the physical bottom of the container. The magnetic mixing member may have a spherical or oblong shape and is caused to rotate within the solution by revolving a pair of magnetic field sources external to the liquid container in a plane above the physical bottom of the container in a generally circular pattern. Rotation of the magnetic field sources is controlled so that the combined magnetic fields acting upon the magnetic mixing member cause it to rotate and generate a mixing motion within the liquid solution. In an exemplary embodiment, the magnetic field sources are diametrically opposed along the sides of and are in close proximity to a false bottom of a liquid sample container and are rotated in a coordinated motion. In an alternate embodiment, the magnetic field sources are rotated at diametrically opposed positions along a liquid sample container and the liquid sample container is moved upwards or downwards relative to the magnetic field sources.
In any of these embodiments, multiple liquid solutions held in liquid containers supported in a rack may be simultaneously mixed by moving the rack through the revolving magnetic fields while the containers remain within the rack. In an exemplary embodiment, the small magnetic mixing member is shaped like a spherical ball and may be automatically dispensed either at time of manufacture of the liquid sample container or loaded on-board the instrument into a liquid solution container easily. Such a spherical mixing member may be produced in large quantities at very low cost so that it may be discarded after a single use in contrast to prior art stirring members that are typically expensive plastic-coated permanent magnets and are therefore repeatedly used, increasing risk of contamination.